The oncoprotein Myc is an important regulator for cell growth and cellular proliferation. When Myc is overexpressed and unregulated, it contributes to the developments of many types of cancers. In a transgenic mouse model, myc overexpression has been shown to result in tumorigenesis. Conversely, the inactivation of Myc in tumor cells causes tumor regression. Previous studies and preliminary data shown here suggest that E2A likely functions as a tumor suppressor, in part, by regulating cell growth and cellular proliferation. I propose to continue to elucidate the molecular mechanism of E2A. In particular, how E2A and Myc are linked to regulate cell growth and cellular proliferation in normal cells as well as tumor cells. In addition, I propose to determine whether E2A can interfere with the cell growth of T-ALL (acute T-cell lymphoblastic leukemia). Specific Aims: (1) to examine how E47 controls cell growth in developing thymocytes (2) to identify potential regulatory elements in the Myc and Mad locus responsive to E47 (3) and to determine whether enforced expression of E47 interferes with the cell growth of T-ALL. Study design: To determine how E47 controls cell growth in developing thymocytes, I will utilize a strategy in which E47 and Myc activity can be manipulated during the beta selection stage or the cell growth stage of thymocyte development. By examining the effects on growth when these activities are interfered, I should be able to determine how E47 and Myc are linked to regulate cell growth in normal cells. To identify potential E47 binding sites at the myc and mad promoters, I will first determine whether E47 binds directly to the promoters to regulate the transcriptions of myc and mads. If E47 binds to the promoters, I will identify the E47 regulatory elements. Once I elucidate the molecular mechanism for E2A tumor suppressor, I will determine whether enforced expression of E47 can interfere with the cell growth of T-ALL cells. I will use a well established murine model for T-ALL and a known human patient T-ALL cell line. Relevance: As mentioned earlier, Myc overexpression is commonly associated with cancer. Therefore, ways to downregulate Myc activity could be potential treatments for cancer. By establishing a molecular mechanism for E2A, we can design drugs that activate E2A activity. With the available human T-ALL mouse model, it will provide a powerful way to screen for drugs that can potentially treat T-ALL as well as other types of cancers.